Erythrokeratodermia is a group of inherited disorders characterized by well-demarcated erythematous lesions and hyperkeratotic plaques. Connexin mutations have been demonstrated to be responsible for most cases of erythrokeratodermia variabilis (EKV). In this condition, we usually observe migratory red patches along with fixed localized or generalized keratotic plaques. Erythrokeratodermia variabilis was also known as Mendes da Costa syndrome. Later, clinical features of progressive symmetric erythrokeratodermia (PSEK), which is known to induce stationary erythematous progressive plaques, were observed within a single family association with EKV features. Therefore, the thinking became that the two diseases (EKV and PSEK) were different manifestations of a single inherited clinical entity. And with the identification of the same gene mutation in patients with EKV and PSEK, some authors proposed the designation of erythrokeratodermia variabilis progressiva (EKVP) to encompass the diversity of the clinical phenotypes of both EKV and PSEK.
Erythrokeratodermia variabilis demonstrates heterozygous dominant inheritance. EKV-associated mutations are usually located in genes encoding either Cx31 (GJB3) or Cx30.3 (GJB4) and occasionally Cx43 (GJA1). These proteins (connexin 31, connexin 30.3 and connexin 43) are gap junction proteins that belong to a large family of transmembrane proteins forming intercellular channels. Gap junctions are responsible for the exchange of metabolites, ions and secondary messengers between cells. The connexin family in humans consists of at least 20 distinct proteins, and most cell types and tissues express more than one connexin gene. Connexin 31 expresses in the skin, peripheral nerves and the cochlea. Cx30.3 expresses in the skin, kidney and pre-implantation blastocyst. Cx43 is ubiquitously expressed. All reported mutations in EKV, are non-conservative amino acid substitution mutations, resulting in impaired epidermal differentiation.
There are reports of rare forms inherited with autosomal recessive modality and caused by homozygous mutations in GJB3 were also described in patients with EKV, although EKV is admittedly a consequence of connexin mutations. Cases with typical features of EKV were not associated with this group of mutations.
In a study by Common et al., molecular investigations of GJB3 and GJB4 were performed in five pedigrees and three sporadic cases of EKV. The detection of connexin 31(Cx31) or connexin 30.3 (Cx30.3) mutations was in only three probands of which two were novel mutations, and one was a recurrent mutation. Also, no mutations in these patients were detected in other epidermal disease-associated Cx genes. The authors conclude that EKV is a heterogeneous condition and individuals clinically diagnosed with this disease harbor different Cx31 or Cx30.3 mutations.
Erythrokeratodermia variabilis lesions are usually present in the first year of life and less frequently since birth. More rarely, EKV occurs later in childhood and even in early adult life. It is a rare disorder, predominantly transmitted in an autosomal dominant manner. The disease shows nearly complete penetrance but with considerable variability. There is documentation of a few cases of autosomal recessive inheritance.
Histopathological examination shows only non-specific findings including papillomatosis, moderate to severe acanthosis, hypergranulosis composed of two to four layer cells, compact hyperkeratosis or parakeratosis, and follicular plugging. In papillary dermis; there are dilated, elongated capillaries with a variable perivascular inflammatory infiltrate. An aspect of suprapapillary thinning is a possible presenting sign, and when it is associated with severe papillomatosis, this may result in a “church spire” configuration of the epidermis. Ultrastructural studies show a decreased number of lamellar bodies in the granular layer.
There are two characteristic types of lesions:
Usually, one of these two features predominates, and occasionally one is missing. Migratory shaped red areas are the initial presenting sign. These lesions are usually well demarcated with a map-like or annular appearance. They can coalesce into large figurate patches, which vary in shape, size, number, and position over minutes, hours, or more often days. A blanched halo may also surround the plaques. Emotional stress, environmental heat or cold, mechanical friction, and sun exposure may cause more prominent erythematous lesions. Stable hyperkeratotic plaques with scaling of the skin evolve simultaneously with or following the development of migratory red patches. These former lesions are usually well-demarcated, yellow to brown and with often a red basis. They are thickened plaques exhibiting a geographic morphology. Sometimes it is so thick and dark that it manifests as a hystrix-like appearance. Moreover, hypertrichosis may present as well as a collarette-like peeling or psoriasiform scales.
Some atypical features of the disease are thought to be a probable clinical variant of EKV. That includes lesions resembling erythema gyratum repens, with a mutation in the Cx30.3 gene identified in these families. Erythrokeratodermia en cocarde is made of circinate or gyrate erythematous patches and have correlations with mutations in GJB4. Some other cases present with erythema annulare centrifugum-like lesions.
The lesions of EKV have a predilection for the extensor aspects of the limbs, buttocks, and the lateral trunk in an almost symmetric distribution. In half of all patients, the thickening of the skin extends onto the palms and soles resulting in palmoplantar keratoderma. Face, scalp, and flexures tend to be spared, but any part of the skin surface may be involved. Skin appendages, like hair, teeth, and nails, are unaffected in this disease and their growth and development progress normally.
Symptoms like a burning sensation in erythematous lesions may cause discomfort in some patients. EKV tends to stabilize after puberty. The duration of the overall condition, however, is lifelong but an improvement over time and periodic clearing of the skin are also possible.
Erythrokeratodermia variabilis is mostly a skin-limited condition. Nevertheless, the evaluation of systemic manifestations is necessary to eliminate other variants of erythrokeratodermia that can mimic EKV clinically. These include KID syndrome with erythrokeratodermia-like lesions. In this condition; keratitis, hearing loss, alopecia and increased susceptibility to infection are present. Moreover, reports exist of neurological symptoms in association with EKV-like lesions including ataxia, and peripheral neuropathy.
Therapy is almost symptomatic and depends on the severity and extent of the hyperkeratosis. Topical management is indicated in mild forms include emollients, topical retinoids, and keratolytic. Systemic retinoids with doses considerably lower compared with those required for other disorders of cornification may be beneficial in some extensive and severe forms. These agents often cause a remarkable improvement and in some cases a complete clearing of the hyperkeratosis. Retinoids show a lower response in relieving erythematous lesions. This latter, often result in cosmetic concerns, which may require by using camouflage makeup. Patients should ideally avoid sudden temperature changes, friction, and irritation.
Recently, novel therapies targeting connexin hemichannels and gap junctions with a direct inhibitory action are being studied and may become available in the future.
Although lesions in erythrokeratodermia variabilis may closely resemble in early stages those of urticaria, differentiating factors include the longer duration of the disease and the occasional presence of scales. When fixed plaques, psoriasis is distinguished by histopathological examination.
In Netherton syndrome, ichthyosis demonstrates migratory, and serpiginous red plaques of that are typical with double-edged scaly borders, and patients usually have other manifestations including hair shaft abnormalities, eczematous lesions, and pruritus. Differential diagnosis also includes different rare types of ichthyosis such as erythrokeratolysis hiemalis, epidermolytic ichthyosis due to KRT1 and KRT10 mutations, and Greither syndrome.
Except for the aesthetic prognosis, erythrokeratodermia variabilis is a begin affection with no extracutaneous manifestations.
Erythrokeratodermia variabilis is a genetically determined condition that can easily be confused with more common dermatoses like psoriasis or urticaria. Pediatricians, as well as dermatologists, primary care physicians, and nurse practitioners, and nurses with specialty training in dermatology should be aware of this condition to provide genetic counseling in families with identified mutations and work in an interprofessional team approach to this rare condition for optimal patient care and clinical results. [Level V]
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